Search

The attenuated yellow fever (YF) vaccine is one of the most successful vaccines ever developed. After a single dose administration YF vaccine can induce balanced Th1/Th2 immune responses and long-lasting neutralizing antibodies. These attributes endorsed it as a model of how to properly stimulate the innate response to target protective immune responses. Despite their longstanding success, attenuated YF vaccines can cause rare fatal adverse events and are contraindicated for persons with immunosuppression, egg allergy and age < 6 months and >60 years. These drawbacks have encouraged the development of a non-live vaccine. The aim of the present study is to characterize and compare the immunological profile of two adjuvant formulations of an inactivated YF 17DD vaccine candidate. Inactivated YF vaccine formulations based on alum (Al(OH)3) or squalene (AddaVax®) were investigated by immunization of C57BL/6 mice in 3-dose or 2-dose schedules, respectively, and compared with a single dose of attenuated YF virus 17DD. Sera were analyzed by ELISA and Plaque Reduction Neutralization Test (PRNT) for detection of total IgG and neutralizing antibodies against YF virus. In addition, splenocytes were collected to evaluate cellular responses by ELISpot. Both inactivated formulations were able to induce high titers of IgG against YF, although neutralizing antibodies levels were borderline on pre-challenge samples. Analysis of IgG subtypes revealed a predominance of IgG2a associated with improved neutralizing capacity in animals immunized with the attenuated YF vaccine, and a predominance of IgG1 in groups immunized with experimental non-live formulations (alum and AddaVax®). After intracerebral (IC) challenge, attenuated and inactivated vaccine formulations showed an increase in neutralizing antibodies. The AddaVax®-based inactivated vaccine and the attenuated vaccine achieved 100% protection, and alum-based equivalent formulation achieved 70% protection. [ABSTRACT FROM AUTHOR]

In Brazil, canine visceral leishmaniasis (CVL) is caused by Leishmania infantum, presenting a broad spectrum of clinical manifestations. Dogs are the main parasite reservoir in urban areas and canine cases precede human infection. Currently, A2 protein-based Leish-Tec® vaccine is the only vaccine commercially available against CVL in Brazil. Considering that the main screening and confirmatory tests of canine infection are serological, it is possible that the antibody response elicited after vaccination interfere with diagnosis, leading to the inability to distinguish between vaccinated and infected animals. In order to identify the specific B-cell response induced after vaccination, A2 protein sequence was screened for main linear B-cell epitopes using in silico prediction (Bepipred) and immunological confirmation by enzyme-linked immunosorbent assay (ELISA). Three amino acid sequences were described as potential B-cell epitopes (PP16-SAEPHKAAVDV, SV11-PQSVGGPLSVGPQSVGP, and VQ34-VGPLSVGPQSVGPLSVGPLSVGPQAVGPLSVGPQ). Specific IgG ELISAs were performed in sera of 12 immunized dogs living in non-endemic areas, followed for up to 1 year after immunization. The results were compared with those obtained in a group of 10 symptomatic and 10 asymptomatic CVL dogs. All predicted epitopes were confirmed as linear B-cell epitopes broadly recognized by sera from studied dogs. Total IgG ELISAs demonstrated distinct patterns of response between peptides in the immunized and CVL groups. VQ34 peptide was recognized by the majority of sera from vaccinated and symptomatic dogs, and increases after vaccination. PP16 induced low levels of specific IgG that increased 1 year after immunization. Interestingly, a low frequency of reactivity was found against SV11 in naturally infected dogs (symptomatic and asymptomatic), while 83.3% of vaccinated dogs presented positive responses 1 year after immunization. The two animals in the vaccinated group that did not respond to SV11 1 year after immunization presented positive serology both 30 days and 6 months after immunization. In summary, we identified three main linear B-cell epitopes in A2-based vaccine. Moreover, the humoral response against SV11 presented marked differences between infected and Leish-Tec® vaccinated dogs and should be further investigated, in large trials, to confirm its potential as a serological marker able to distinguish between infected and vaccinated dogs. [ABSTRACT FROM AUTHOR]

There have been exhaustive efforts to develop an efficient vaccine against leishmaniasis. Factors like host and parasite genetic characteristics, virulence, epidemiological scenarios, and, mainly, diverse immune responses triggered by Leishmania species make the achievement of this aim a complex task. It is already clear that the induction of a Th1, pro-inflammatory response, is important in the protection against Leishmania infection. However, many questions must still be answered to fully understand Leishmania immunopathology, especially regarding Leishmania-specific Th1 response induction, regulation, and persistence. A large number of Leishmania antigens able to induce pro-inflammatory response have been selected so far, but none of them demonstrated efficiency in protection assays. A possible explanation is that CD4 T cells display marked heterogeneity at a single-cell level especially regarding the production of Th1-defining cytokines and multifunctionality. It has been established in the literature that Th1 cells undergo a differentiation process, which can generate cells with diverse phenotypes and survival capabilities. Despite that, only a few studies evaluate this heterogenic response and the amount of multifunctional CD4 T cells induced by Leishmania vaccine candidates, missing what can be a crucial point in defining a correlate of protection after vaccination. Moreover, most of the knowledge involving the development of cutaneous leishmaniasis (CL) vaccines comes from the mouse model of infection with Leishmania major, which cannot be fully applied to New World Leishmaniasis. For this reason, the immune response triggered by infection with New World Leishmania species, as well as vaccine candidates, need further studies. In this review, we will reinforce the importance of evaluating the quality of immune response against Leishmania, using a multiparametric analysis in order to understand better this complex host-parasite interaction, discussing the differences in the responses triggered by different New World Leishmania species, as well as the impact on the development of an effective vaccine against CL. [ABSTRACT FROM AUTHOR]